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Pharmaceutics
Special Issues
Pharmaceutical Solid Forms: From Crystal Structure to Formulation
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Pharmaceutical Solid Forms: From Crystal Structure to Formulation

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: 20 January 2025 | Viewed by 8955

Special Issue Editor

Dr. Philippe Espeau

E-Mail Website
Guest Editor
UTCBS, Department of Pharmacy, University Paris Cité, 75006 Paris, France
Interests: pharmaceutical compound; solid state; relative stability; phase diagrams; thermodynamics; thermal analyses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Before it becomes beneficial for the patient, a drug must go through several phases of development. Its final formulation, where the active ingredient is mixed with the other components (excipients), must take into account various factors, such as its solid state, pH, solubility, etc. Indeed, in the solid state, the active ingredient can exist in different forms: anhydrous or solvated crystalline, non-crystalline (amorphous), or even in the form of salts or, more rarely, in the form of co-crystals. It should be remembered that more than 80% of drugs exist in solid form and that almost all of the active ingredients are solid in the raw material state. The solid form may affect the chemical and physical properties of the drug, mostly physical and/or chemical stability (including pharmaceutical operations), solubility, bioavailability, etc. Consequently, the identification and control of the API solid form in the final drug must be ensured throughout the development, including final packaging. Indeed, the active substance may interact physically or chemically with the excipients, or with the container, which may modify its activity.

For stability reasons, it is always preferable to formulate a drug from its most stable solid form. Relative stability is assessed based on various parameters, such as temperature, pressure, water content, pH, etc. However, due to insufficient bioavailability, it may be necessary to formulate a less stable solid form. It will then be necessary to seek to stabilize this metastable form using the right excipients. The physical properties of the active ingredient, and then its crystal structure, have to be characterized using various techniques (X-ray powder diffraction, thermal analyses, etc.) to determine which solid form will be formulated.

Dr. Philippe Espeau
Guest Editor

Manuscript Submission Information

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Keywords

  • solid state
  • characterization techniques
  • polymorphism
  • solvates
  • hydrates
  • preformulation
  • drug stability

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Published Papers (5 papers)

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Research

12 pages, 3943 KiB  
Article
Hydrogen Bonding in Amorphous Indomethacin
by C. J. Benmore, J. L. Yarger, S. K. Davidowski, C. D. Shrader, P. A. Smith and S. R. Byrn
Pharmaceutics 2024, 16(8), 1002; https://doi.org/10.3390/pharmaceutics16081002 - 29 Jul 2024
Viewed by 1011
Abstract
Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, [...] Read more.
Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, that are consistent with their high-energy X-ray diffraction patterns. It is found that the majority of molecules in amorphous Indomethacin are non-bonded or bonded to one neighboring molecule via a single hydrogen bond, in contrast to the doubly bonded dimers found in the crystalline state. The EPSR models further indicate a substantial variation in hydrogen bonding between different amorphous forms, leading to a diversity of chain structures not found in any known crystal structures. The majority of hydrogen bonds are associated with the carboxylic acid group, although a significant number of amide hydrogen bonding interactions are also found in the models. Evidence of some dipole–dipole interactions are also observed in the more structurally ordered models. The results are consistent with a distribution of Z-isomer intramolecular type conformations in the more disordered structures, that distort when stronger intermolecular hydrogen bonding occurs. The findings are supported by 1H and 2H NMR studies of the hydrogen bond dynamics in amorphous Indomethacin. Full article
(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)
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18 pages, 4244 KiB  
Article
Enhanced Stability and Compatibility of Montelukast and Levocetirizine in a Fixed-Dose Combination Monolayer Tablet
by Tae Han Yun, Moon Jung Kim, Jung Gyun Lee, Kyu Ho Bang and Kyeong Soo Kim
Pharmaceutics 2024, 16(7), 963; https://doi.org/10.3390/pharmaceutics16070963 - 21 Jul 2024
Viewed by 1692
Abstract
The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in [...] Read more.
The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in the appearance characteristics and impurity content were observed in a dry oven at 60 °C. Excipients that contributed minimally to impurity increases were selected to minimize drug interactions. Mannitol, microcrystalline cellulose, croscarmellose sodium, hypromellose, and sodium citrate were chosen as excipients, and montelukast–levocetirizine FDC monolayer tablets were prepared by wet granulating the two drugs separately. A separate granulation of montelukast and levocetirizine, along with the addition of sodium citrate as a pH stabilizer, minimized the changes in tablet appearance and impurity levels. The prepared tablets demonstrated release profiles equivalent to those of commercial products in comparative dissolution tests. Subsequent stability testing at 40 ± 2 °C and 75 ± 5% RH for 6 months confirmed that the drug content, dissolution rate, and impurity content met the specified acceptance criteria. In conclusion, the montelukast–levocetirizine FDC monolayer tablet developed in this study offers a potential alternative to commercial products. Full article
(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)
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15 pages, 2947 KiB  
Article
Investigation of the Storage and Stability as Well as the Dissolution Rate of Novel Ilaprazole/Xylitol Cocrystal
by Sihyun Nam, Changjin Lim, Yongdae Kim, Bokyoung Yoon, Taewoo Park, Woo-Sik Kim and Ji-Hun An
Pharmaceutics 2024, 16(1), 122; https://doi.org/10.3390/pharmaceutics16010122 - 17 Jan 2024
Cited by 1 | Viewed by 1653
Abstract
Reflux esophagitis, a treatment for gastric ulcers known as Ilaprazole (Ila), is not stable during storage and handling at room temperature, requiring storage at 5 degrees Celsius. In this study, to address these issues with Ila, coformers rich in oxygen (O) and hydroxyl [...] Read more.
Reflux esophagitis, a treatment for gastric ulcers known as Ilaprazole (Ila), is not stable during storage and handling at room temperature, requiring storage at 5 degrees Celsius. In this study, to address these issues with Ila, coformers rich in oxygen (O) and hydroxyl (OH) groups capable of forming hydrogen bonds with were selected. These coformers included Xylitol (Xyl), Meglumine (Meg), Nicotinic acid (Nic), L-Aspartic acid (Asp), and L-Glutamic acid (Glu). A 1:1 physical mixture of Ila and each coformer was prepared, and the potential for cocrystal formation was predicted using differential scanning calorimetry (DSC) screening. The results indicated the potential for cocrystal formation in the Ila/Xyl physical mixture. Subsequently, Ila and Xyl were mixed in ethyl acetate (EA) in a 1:1 ratio, and after 28 h of slurry, the formation of Ila/Xyl cocrystal was confirmed through solid-state CP/MAS 13C NMR spectrum analysis, showing intermolecular hydrogen bonding and conformational changes. Furthermore, the 1:1 ratio of Ila/Xyl cocrystal was confirmed through solution-state NMR (1H, 13C, and 2D) molecular structure analysis. To assess the stability of Ila/Xyl cocrystal at room temperature, it was stored and compared with Ila at 25 ± 2 °C and relative humidity (RH) of 65 ± 5% over three months. The results showed that the purity of Ila/Xyl cocrystal remained at 99.8% from the initial purity of 99.75% over the three months, while Ila was predicted to decrease from an initial 99.8% purity to 90% after three months. Additionally, at 25 ± 2 °C and RH 65 ± 5%, a specific impurity B in Ila/Xyl cocrystal was observed to be 0.03% over three months, whereas Ila was predicted to increase from an initial 0.032% to 2.28% after three months. To evaluate the dissolution rate of Ila/Xyl cocrystal, a formulation was prepared and compared with Ila at pH 10, with a dosage equivalent to 10 mg of Ila. The results showed that Ila/Xyl cocrystal reached 55% within 15 min and 100% within 45 min, while Ila was predicted to reach 32% at 15 min and 100% only after 60 min. However, overall, the Ila/Xyl cocrystal showed results equivalent to or exceeding the dissolution rate of Ila. Therefore, it is predicted that the Ila/Xyl cocrystal will maximize its effectiveness as a more convenient crystal structure for formulation development, allowing storage and preservation at room temperature without the need for the problematic 5 °C refrigeration during ambient conditions and storage, addressing the issues associated with Ila. Full article
(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)
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12 pages, 5910 KiB  
Article
Impact of Poloxamer on Crystal Nucleation and Growth of Amorphous Clotrimazole
by Jie Zhang, Ziqing Yang, Liquan Luo, Kang Li, Taotao Zi, Junjie Ren, Lei Pan, Ziyue Wang, Zihao Wang, Minzhuo Liu and Zhihong Zeng
Pharmaceutics 2023, 15(8), 2164; https://doi.org/10.3390/pharmaceutics15082164 - 21 Aug 2023
Cited by 3 | Viewed by 1449
Abstract
Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, [...] Read more.
Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal–liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs. Full article
(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)
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13 pages, 7259 KiB  
Article
Evidence of a New Crystalline Phase of Prednisolone Obtained from the Study of the Hydration–Dehydration Mechanisms of the Sesquihydrate
by Aurélien Lemercier, Nicolas Couvrat, Yohann Cartigny, Morgane Sanselme, Yohann Corvis, Philippe Espeau and Gérard Coquerel
Pharmaceutics 2023, 15(6), 1694; https://doi.org/10.3390/pharmaceutics15061694 - 9 Jun 2023
Cited by 1 | Viewed by 1600
Abstract
The dehydration of prednisolone sesquihydrate is studied and characterized by different physico-chemical analysis methods. The meticulous study of this dehydration led to the highlighting of a new solid form (form 3), metastable, never identified before. In a second step, the rehydration of anhydrous [...] Read more.
The dehydration of prednisolone sesquihydrate is studied and characterized by different physico-chemical analysis methods. The meticulous study of this dehydration led to the highlighting of a new solid form (form 3), metastable, never identified before. In a second step, the rehydration of anhydrous forms 1 and 2 of prednisolone is studied, in particular by Dynamic Vapor Sorption. It is then demonstrated that neither of the two forms is sensitive to humidity. By means of solid-gas equilibria, the sesquihydrate can only be obtainable from the isomorphic anhydrous form. Finally, a classification of the sesquihydrate is made, taking into account, in particular, the activation energy determined during dehydration. Full article
(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)
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